Substance use among adolescents continues to be highly prevalent in the US. Likewise, many adolescents engage in sexual behaviors that place them at elevated risk for HIV and other sexually transmitted infections. Screening, brief intervention, and referral to treatment (SBIRT) is a promising approach for integrating substance use services into healthcare settings. School-based health centers (SBHCs) are a rapidly expanding model of healthcare delivery offering health services far beyond those of the traditional school health office. Implementing SBIRT in SBHCs could have major public health benefits, but research is needed to identify the most effective way to deliver SBIRT for adolescents in these settings. Two approaches for SBIRT that are particularly promising in their practicality, scalability, and sustainability are nurse practitioner-delivered brief intervention ad computer-delivered brief intervention. We propose to conduct a randomized controlled trial to determine the comparative clinical effectiveness and cost-effectiveness of these two approaches in reducing marijuana use, alcohol use, and sex risk behaviors. The study will be conducted in SBHCs embedded within two public high schools in Baltimore, Maryland. SBHC patients ages 14-18, inclusive, will be screened for eligibility by research staff with the CRAFFT, a brief substance misuse screening instrument recommended by the American Academy of Pediatrics. The study will enroll 300 male and female adolescents who report risky marijuana or alcohol use. Participants will be randomly assigned to receive a nurse practitioner-delivered brief intervention (NBI) consisting of brief motivational advice as part of their medical visit, ora promising interactive computer-delivered brief intervention (CBI) based on motivational interviewing. Both intervention conditions will include HIV risk reduction content tailored based on individual risk factors, and both conditions will include a referral pathway for additional substance abuse assessment and possible treatment by specialized substance abuse treatment staff. Research assessments will be conducted at baseline and at 3- and 6-month follow-up, and will gather self-reported data on substance use and sexual risk behaviors. A focused economic analysis will compare the NBI and CBI conditions with respect to their incremental cost-effectiveness for selected primary behavioral outcomes and for quality-adjusted life years (QALYs). A qualitative process evaluation will examine adolescent participants' and SBHC staff members' perspectives on the competing BI strategies. This study has the potential for significant public health impact because it could identify the most effective SBIRT model for addressing adolescent substance use and HIV risk behaviors, both of which can have major health repercussions in the near-term and over the lifespan. The study is highly innovative in its focus on SBHCs, a rapidly expanding healthcare model that is uniquely suited to maximize the impact and reach of SBIRT for adolescents. It will be the largest randomized trial of SBIRT in US high schools, the first study of SBIRT in SBHCs, and the first study of SBIRT for adolescents in any setting to include an economic analysis.